title: p16INK4a expression and absence of activated B-RAF are independent predictors of chemosensitivity in melanoma tumors.
abstract: Metastatic cutaneous melanoma is highly resistant to cytotoxic drugs, and this contributes to poor prognosis. In vivo studies on the chemosensitivity of metastatic melanoma are rare and hampered by poor response rates to systemic chemotherapeutics. Patients who undergo isolated limb infusion (ILI) with cytotoxic drugs show high response rates and are, therefore, a good cohort for studying chemosensitivity in vivo. We used tumors from patients who underwent ILI to study the role of melanoma tumor-suppressor genes and oncogenes on melanoma chemosensitivity. Prospectively acquired tumors from 30 patients who subsequently underwent ILI with melphalan and actinomycin-D for metastatic melanoma were investigated for mRNA expression levels of p14(ARF), p16(INK4a), and MITFm. The mutation status of B-RAF, N-RAS, and PTEN were also determined. A high percentage of tumors had activating mutations in either B-RAF (15/30) or N-RAS (10/30) and only two tumors carried altered PTEN. High expression of p16(INK4a) and absence of an activating B-RAF mutation independently predicted response to treatment. Further, inducible expression of p16(INK4a) sensitized a melanoma cell line to death induced by melphalan or actinomycin-D. This study shows that high expression of p16(INK4a) or the absence of activated B-RAF correlates with in vivo response of melanoma to cytotoxic drugs.
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead NSW 2145, Australia.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Gallagher
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: James
authors.initials: J
authors.lastname: Indsto
authors.forename: Lyndee L
authors.initials: LL
authors.lastname: Scurr
authors.forename: Margaret
authors.initials: M
authors.lastname: Lett
authors.forename: Bo-Fu
authors.initials: BF
authors.lastname: Gao
authors.forename: Ruth
authors.initials: R
authors.lastname: Dunleavey
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002453:Cell Cycle; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D003609:Dactinomycin / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D011905:Genes, ras; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics*; D008558:Melphalan / Q000627:therapeutic use; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D018807:Polymorphism, Single-Stranded Conformational; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D025803:Tumor Suppressor Protein p14ARF; D003609:Dactinomycin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D008558:Melphalan